Nalmefene [17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol] has the following general formula:
and can be prepared using methods that are well known in the art e.g. starting by manufacturing of naltrexone from noroxymorphone as described in WO 2012/059103 and subsequently manufacturing nalmefene from naltrexone e.g. by the Wittig reaction as described in WO 2010/136039. The entire contents of each of WO 2012/059103 and WO 2010/136039 are incorporated herein by reference.
Nalmefene is a known opioid system modulator, with a distinct μ, δ, and κ receptor profile, which can inhibit pharmacological effects of both administered opioid agonists and endogenous agonists derived from the opioid system. The clinical usefulness of nalmefene comes from its ability to promptly and selectively reverse the effects of these opioid agonists.
Nalmefene has primarily been developed for use in the management of alcohol dependence. A double-blind, placebo-controlled study has shown good effect of 20 to 80 mg daily oral dosing of nalmefene (Mason et al., Arch. Gen. Psychiatry, (1999), Vol. 56: 719-724); while another study reported no evidence of superiority of nalmefene over placebo in a study evaluating 5, 20 and 40 mg daily doses of nalmefene (Anton et al., J. Clin. Psychopharmacol., (2004), Vol. 24(4): 421-428). A more recent study, showed good effect of nalmefene over placebo when a dose of 20 mg nalmefene was taken when the patient experienced a craving for alcohol (Karhuvaara et al., Alcohol. Clin. Exp. Res., (2007), Vol. 31 (7): 1179-1187).
Based on independent evidence, high levels of alcohol consumption are associated with an increased risk of health-related harm, as well as adverse social consequences. The World Health Organization (WHO) has defined drinking risk levels (DRLs) based on alcohol consumption in International Guide for Monitoring Alcohol Consumption and Related Harm. 2000. World Health Organization, the entire contents of which are incorporated herein by reference. See Table 1.
TABLE 1WHO Drinking Risk Levels (DRLs) of Alcohol ConsumptionTotal Alcohol Consumption (g/day)DRLMenWomenVery high risk>100>60High risk>60 to 100>40 to 60Medium risk>40 to 60 >20 to 40Low risk1 to 401 to 20
Risk levels according to Table 1 can be assessed e.g. by calculating mean daily alcohol consumption in g/day over a month such as over 4 weeks. There is a need for a new treatment for use in reduction of alcohol consumption. Reduction of alcohol consumption is likely to provide benefits associated with decreased risk of health-related harm and decreased number of adverse social consequences.